Acute sex difference in response to repeated mild traumatic brain injury in mice

Acute sex difference in response to repeated mild traumatic brain injury in mice

Aaron Kuo, Philip Vann, Nathalie Sumien, Ahmed Affan, Derek Schreihofer

Background: Repetitive mild traumatic brain injury (rmTBI), such as that occurring in contact sports, is associated with the development of neurodegenerative diseases of aging. Severe TBI and repetitive concussions are associated with chronic traumatic encephalopathy (CTE), Alzheimer’s disease (AD), and Parkinson’s disease (PD), among others. However, less severe injuries may also lead to delayed neurological disfunction if repeated often and without sufficient rest time between injuries. Previously, we found that the progression of behavioral deficits in males and female mice differed from 5 to 15 weeks after 25 rmTBI. Both sexes showed motor deficits at 5 weeks, but only males showed affective and cognitive deficits at 15 weeks.

Purpose: This study tested the hypothesis that rmTBI neurological deficits in male mice will appear earlier after rmTBI than in female mice.

Methods: C57BL/6 male and female mice (8 wk old) were assigned to sham and rmTBI groups (n=20/group). Lightly anesthetized mice received 7 mild head injuries, once a day (M-F) using a weight drop model (75 g from 1 meter) that included a free fall with rotational injury. Five minutes after the final injury, mice were tested on a balance beam. Additional behavioral assessments began the following day.

Results: No sex differences in balance beam performance were observed 5 minutes after the final injury. There were no significant effects of rmTBI on vestibular motor function assessed with a rotarod; cognition assessed with the Morris water maze; or affective behavior assessed with the elevated plus maze. However, in the open field test there was a significant increase in total distance traveled in rmTBI mice (F1,35 = 6.47, P=0.016). Post-hoc analysis revealed that this effect was only significant in male mice (Fisher LSD, P<0.05), supporting the hypothesis that males exhibit earlier deficits than females.

Conclusion: At extended time points following rmTBI, both male and female mice develop motor deficits. However, up to 15 weeks after injury, only male mice experience cognitive and affective deficits. The current study reveals that male mice also display hyperactivity in the week after rmTBI that is not observed in female mice. Thus, sex differences in response to rmTBI are apparent both in the acute and chronic phase of injury and suggest that interventions to reduce brain injury may require different timing for males and females. Ongoing studies are examining potential differences in biochemical and histological responses in the brains of male and female mice.

AUP: 2021-0035